Triazine derivatives of diphenyl sul



Patented June 3, 1952 ,7

TRIAZINE DERIVATIVES OF DIPHENYL SUL- FONES, SULFOXIDES, AND SULFIDES, :AND METHODS OF PRODUCTION Ruth H. Vogel, New York, N. Y.

No. Drawing. Application. August 1 6, 1951,

, ,SetialNo. 249,606 1 p I This invention relates to compounds oI'the-gcneral formula in which X is a member of the group consisting :6 Claims. (Cl. 260-23917) 0.1502, SO, and S, R is a .member of thegroup consisting of hydrogen and a substituted or unsubstituted hydrocarbon radicaLR' is a member of the group consisting of'hydrogenand an alkyl radical, and Y is a member of the group consisting ofi a substituted or .unsubstituted amino radical an; "N02; and to the process of making them. These 'new products are found to be effective antibacterial agents.

It is the object of thepresent inventionto provide new and useful organic compounds. 'It is a further object to provide new and therapeutic compounds active against bacteria, particularly Mycobacterz'um tuberculosis. Other objects will appear hereinafter.

It is commonly believed that antibacterialcompounds of the-general type of N-substituted derivatives of 4,4"-diaminodiphenyl sulfone .andrelated compounds owe their activity to removal of the substituents and liberation of the active parent amino compound by catabolic processes; N --heterocyclic --substituted compounds of this type, however, are not considered to be thus cleavableand thought to be inactive per se (see, for example, E; H. 'Northey, The Sulfonam'ides and Allied Compounds Reinhold Publishing Corportation, New York, 1948, pp. 341,344). Comtrary to expectations, it'has been found that the N-1heterocyclicsubstituted derivatives of .4,4"-diaminodi'phenyl sulfone and related compounds described herein are powerful antibacterial agents; for example, p-fZA-diamino s-triaZinyl- 6') -aminophenyl p'aminophenyl sulfone-is even more active against Mycobacterium tuberculosis than 4,4 -diaminodiphenyl sulfone.

According to the present invention, the new compoundsare generallyobtained by reacting unsubstituted or appropriately substituted 2,4-diamino-6-chloro-s-triazine with a 4,4'disubstituted dipheny-l sulfone, or analogous sulfoxide or sulfide, in which at least one of the substituents is an amino group having at least one hydrogen atom capable of replacement. The-invention is illustrated by the following examples diamino '-"s triazinyl '6) 'aminophenyl-l ionejwhich is removed by filtration "and has "-a '2 C5, deposits "the dihydrochloride of his iii-(2;:-

dry weight of 19.1 g. The filtrate, on keeplng at 5 C. .for 72 "hours, yields"the 'dihydrochloride of p (2;4 diamino s triazinyl 6) aminophenyl p-aminophenyl sulione, which is isolated by flltrationiand has :a dry" weight of 22.4 :g. The formation of 'this'product maybe represented as follows:

The product is recrystallized by dissolving it in 1 ll. boiling water, adding '500' ml. concentrated hydrochloric acid, and chilling. The (resulting white material is Jfiltered, washed with ice-cold '4 normal hydrochloric acid and acetone, dried in vacuo,andweighs 21.4 g. I p

12 g. of this dihydrochloride are dissolved in 600 ml. hot water. To the resulting clear solution is added with stirring a solutionoi. .458 g. anhydrous sodium carbonatein'120 mlrwater. A soft precipitate of p-(2,4-diamino-setriazinyl 6) eaminophenyl p-.aminophenyl sulfone' in the form of the free base is obtained which. 'hard'ens on chilling. After filtering and washing with water, the product is further purified .by grinding with water to form. a thin paste, filtering again, washing with water, and drying invacuo. The yield is 8.8 g. The free .base is a white powder which is only slightly soluble in water, sparingly soluble. in dilute hydrochloric acid, and soluble in propylene glycol. When sodium nitrite is added to a cold acid solution of this product, a diazonium salt formed. The diazotized product couples with 'R-salt in the presence of alkali and with other compounds capable of undergoing a coupling reaction. When heated rapidly, the base melts at approximately 240-245' C.

Example 2.--A mixture of 2.48 g. (0.01 mole) 4,4-diaminodiphenyl sul'fone, ml. water. .3 ml. concentrated hydrochloric acid, and 2.91 g. (0.02 mole) 2,4-diamino-6-chloro-s'-triazine is boiled for 10 minutes and then cooled. Theresulting white precipitate of the dihydrochloride of his [p- 2,.4-diamino s-tri'azinyl-G) -a'minophen.- yll- :sulione is filtered on paper. washed. with dilute hydrochloric acid and acetone." and: is

described; in Example 1.

dried The productrformed in high 7 yield has the formula I NH:

It may be recrystallized from dilute hydroaqueous solution oi sodium carbonate. or another suitable basic compound, substantially. as This free base is a white, powder which does-not melt at 250 C.

Example 3.0.-16 mole 4 amino 4'-nitrodiphenyl sulfoneis reacted with 0.16 mole 2,4-

-diamino-G-chloro-s-triazine substantially as described in Example 1. The resulting product, the 'monohydrochloride of p-(2,4-diamino-striazinyl-6)-aminophenyl p'-nitrophenyl sulfone, is reducible by the action of a suitable reducing agent, for example, by heating with an excess of 'tin in dilute hydrochloric acid, to form 'p- (2,4-diamino-s-triazinyl-6) -aminophenyl aminophenyl sulfone in the form of a salt.

Example 4.-4,4'-diaminodiphenyl sulfoxide is reacted with 2,4-diamino-fi-chloroes-triazine substantially as described in Example 1.

Example -,5.- -4,4-diaminodiphenyl sulfide is reacted with 2,4-diamino-fi-chloro-s-triazine substantially as described in Example 1.

Example 6.-4-amino-4'-nitrodiphenyl sulfoxide is reacted with 2,4-diamino-6-chloro-striazine substantially as described in Example 3. .Erample 7.--.4-amino-4-nitrodiphenyl sulfide is reacted with 2,4-diamino-6 chloro-s-triazine substantially as described in Example 3.

In Examples 1 and 2, the ratio of 2,4-diaminofi-chloro-s-triazine to 4,4' diaminodiphenyl sulfone may be less thanl'or greater than 2 respectively. In the .above examples, instead of hydrochloric acid, another mineral acid such as sulfuric acid, oran organic acid such as tartaric acid, may be used and the amount of acid may be varied. Instead of carrying out the reactions'ldescribed at the boiling point, another temperature may be used, preferably above 60 9.. The duration of the heating period may be varied within wide limits.

' In the above examples, instead of unsubstituted 2,4-diamino-6-chloro-s-triazine there may be used .a -2,4-diamino-6-chloro-s-triazine sub- 'stituted by" one. or more lower alkyl, alkenyl, hydroxyalkyl, "and 'carboxyalkyl radicals, for example, 2-amino-4-propylamino 6 chloro-striazine, 2-amino-4-allylamino-6-chloro-s-triazine, 2 e amino 4 (2' hydroxyethylamino) -6- chloro s triazine, 2 amino-4-carboxymethylamino-6 chloro-s-triazine, 2,4 di (methylamino) -6-ch1oro?s-triazine, and 2,4-di-(ethylamino) -6-chloro-s-triazine, giving products analogous to those of the above examples.

Instead of using as reactants the 4,4'-disubstituted. diphenyl sulfones, sulfoxides and sulfides' having one or two unsubstituted amino groups set forth above, there may be used such sulfones, sulfoxides and sulfides, inrwhich one or both'of the amino groups are substituted by one or more lower alkyl radicals, including among others 4 ami no 4-methylaminodiphenyl sulfone, 4-amin'o-'-ethylaminodiphenyl sulfone, 4 aminc 4 diphenyl sul fone, 151 (methylamino) diphenyl sulfone, "4'-nitro-4'-'ethylami- 10 nodiphenyl sulfone, and 4-nitro-4'-methylaminodiphenyl sulfoxide, giving products analogous to those of the above examples.

The invention may be variously otherwise embodied within the scope of the appended claims.

I claim: a

1. A compound having the formula ZN l N o-N- -xy f NE,

in which X is a radical, selected from th group consisting'of $02, $0, and S, and Ypis a, radical selected from the group consisting of NH2, N02, and 2,4-dia'mino-s-triazinyl-6-amino.' 1 I 2. The compound p-(2,4-diamino-s-triazinyl- 6) -aminophenyl p-aminophenyl sulfon-e.

3. The compound bislp-(2,4-diamino-s-triazinyl-6)-aminophenyl] sulfone.

4. The process which comprises reacting 2,4- diamino-6-chloro-striazine. With an aromatic amino compound of the general formula in which X is a radical selected from the group consisting of $02, $0, and S, and Y is a radical selected from the group consistingof NHz and N02, by heating said. reactants in aqueous solutionin the presence of an acid, thereby causing substitution of at least one amino group of said aromatic amino compound by one 2,4-diaminos-triazinyl-G radical with elimination of hydrochloric acid. l

5. The process which comprises reacting one molar equivalent of 2,4-diamino-6-chloro-s-triazine with substantially one molar equivalent of 4,4'-diaminodiphenyl sulfone by heating said reactants in aqueous solution at the boiling point in the presence of hydrochloric acid, and recovering the product, p-(2,4-diamino-s-triazinyl-6)- aminophenyl p'-aminophenyl sulfone.

6. The process which comprises reacting two molar equivalents of 2,4-diamino-6-chloro-s-triazine with substantially one molar equivalent of 4,4'-diaminodiphenyl sulfone by heating said reactants in aqueous solution at the boiling point ing the product, bislp-(2,4-diamino-s-triazinyl- 6) -aminophenyll sulfone.

- RUTH H. VOGEL.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS in the presence of hydrochloric acid, and recover-, 

1. A COMPOUND HAVING THE FORMULA 